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Topical interferon alpha in atopic eczema
EISEVIER
Journal of the European Academy of Dermatology and Venereology 5 (1995) 153-156
JEADV
Topical interferon alpha in atopic eczema Brigitte Cremer * , Corinna Kohlmus, Beate M. Czarnetzki Department of Dermatology,
University Clinic Rudolf virchow, Freie Universitiit Berlin, Augustenburgerplatz D 13344 Berlin, Germany
1,
Abstract Background On the basis of experimental and clinical data, interferon (Y might improve pathological alterations in atopic eczema. Systemic treatment with this drug is however cumbersome and fraught with side effects. Objective Since most patients with atopic eczema have only localized disease, we have decided to study the effect of topically applied interferon (Y in this disease. Design A pilot study was performed on 10 patients, using a single-blind, within-patient comparison. An interferon-cw2a gel formulation (150000 IU/g) was studied against triamcinolone acetonide, liquor carbonis detergens and bland cremes or gels with a twice daily application to the anticubital fossae over 10 days. Biopsies were taken from 3 patients for evaluation of treatment-induced histopathological changes. Results Improvement of eczema occurred most rapidly with triamcinolone whereas interferon (Y was as effective as other treatments and vehicle alone. No effect on pruritus was noted with any patient, Only two patients considered interferon (Ybetter than liquor carbonis detergens or bland cremes respectively. Mast cell numbers were elevated in all patient biopsies and were lower on the triamcinolone-treated site in only one patient. Conclusion Short-term treatment with topically applied interferon (Y is thus ineffective in atopic eczema. Keywords: Atopic eczema; Interferon a; Mast cells; Corticosteroids; Liquor carbonis detergens
1. Introduction The treatment of atopic eczema presents a major therapeutic challenge since all currently available treatment modalities suppress symp* Corresponding author.
toms only transiently or side effects are unacceptable [l]. Avoidance of allergens is the best preventive measure but is mostly impracticable. Since the basic pathology of atopic eczema involves defects in the immune system, with overactivity of IgE-dependent processes, treatment with immunomodulating agents such as cortico-
0926-9959/95/$09.50 0 1995 Elsevier Science B.V. AU rights resewed SSDZ 0926-9959(95)00081-X
154
B. Cremer et al. /J. Eur. Acad. Dennatol.
steroids and cyclosporin A has been found to be highly effective, although side effects prohibit long-term use of these agents [1,21. Interferons (IFN) have recently been reported to suppress IgE synthesis in vitro [3] and to possibly affect IgE levels and eczema in vivo [4]. Several clinical studies have since yielded no or only minor clinical benefits, no decrease of IgE levels, and only few changes in other laboratory parameters like eosinophil numbers [5-91. Treatment is generally well tolerated despite the cumbersome injections, with mostly only transient flu-like symptoms. Explanations for the discrepancy between in vitro and in vivo observations might be insufficient concentrations of the drug at the tissue level. Since the majority of patients with atopic eczema suffer from limited involvement of their skin and in order to obtain a higher local drug concentration, we have decided to conduct a pilot study using a gel formulation of IFNa in comparison with established, locally effective treatment modalities and bland formulations. 2. Methods Ten hospitalized patients (5 males and 5 females; mean age 38.5 and 23.5 yrs respectively) with mild to moderately severe atopic eczema agreed to participate in the study. All patients had a personal and 9 of them also a family history of atopic diseases. Mean serum IgE levels were 10000 IU/ml (range 600-35000) and mean serum eosinophilia 20%. No other abnormal laboratory findings were noted. An IFNa gel formulation at 150000 IU/g was prepared by the hospital pharmacist, mixing: 1. five ampules containing 3 mil IU IFNa2a (RoferonR); 2. hydroxyethylcellulose 10000, 2.5 g; 3. glycerol 85%, 10 g; 4. distilled water ad 100 (formulation kindly provided by Prof. R. Stadler, Minden, Germany). This formulation is stable at 4°C for 4 weeks. The gel was applied twice daily over 10 days on skin of the anticubital fossa. On the contralatera1 side, patients received the following substances at the same frequency: the gel base of the
Venereal. 5 (1995) 153-156
IFN formulation (2 patients); triamcinolone acetonide in adeps lanae, 0.1% (3 patients); liquor carbonis detergens 10% (2 patients); a bland creme base (3 patients). Blinding was for patients only. They were asked daily regarding itching and tolerance of the medication at each treated site, and the physician evaluated changes in intensity of local inflammation and extent of the lesions. At the end of treatment, three patients (all tested against triamcinolone) agreed to have biopsies taken which were processed for routine histology and stained with H&E and with toluidine blue O.l%, pH 0.5, overnight for mast cell counts. Biopsies from the same sites were taken from 3 non-atopic normal controls. Sections were evaluated by 3 independent observers and cell counts performed at 400 x magnification in at least two microscopic fields directly underlying the epidermis. Data are expressed as means f 1 standard deviation (SD). 3. Results All lesions improved within 5-6 days, except for triamcinolone acetonide-treated sites where healing occurred already within 3-4 days. The within-patient comparison of the two treated sites showed no differences in intensity of itching, except for increased pruritus in one patient treated with IFNa (Table 1). Regarding subjective tolerance, two patients considered the IFNa-gel better compared to LCD and bland creme, respectively, and one patient found the IFNa-gel worse than triamcinolone. Table 1 Comparison of clinical effects of IFNa-containing gel in comparison to either of the various agents shown above, applied to the contralateral antecubital fossa of patients with atopic eczema. Numbers indicate patients where the compared substance was better or worse than IFNa. In the remaining cases, effects were the same on both arms Agents tested against IFNa (N)
Pruritus
Eczema
Tolerance
Better Worse Better Worse Better Worse
Triamcinolone (3) 0 LCD (2) 0 Bland ointment (3) 0 Gel base (2) 0
0 0 1 0
3 0 1 0
0 1 0 0
1 2 0 0
0 0 0 0
B. Cremer et al. /.I. Eur. Acad. Dermatol. Venereol.5 (1995) 153-156 Table 2 Mast cell counts/microscopic field (4OOXmagn.) from biopsies of the antecubital fossa in patients after the lo-day treatment and in normal controls Biopsies (N) from Patients, IFNa-treated side (3) Patients, steroid-treated side (3) Normal controls (3)
Mast cell numbers Means f SD
Range
47.3 + 16.4
(25-64)
40.0 + 13.5
(24-57)
22.7* 2.6
(17-25)
On histological evaluation, all patients exhibited typical features of atopic eczema on H&E, compared to normal skin, despite the preceding treatment, with acanthosis and a moderate perivascular inflammatory infiltrate consisting of lymphocytes and macrophages. Eosinophils were not seen. Mast cell numbers were elevated in patient compared to normal skin (Table 2). Numbers were only slightly higher at IFNa compared to triamcinolone-treated sites, without reaching statistical significance. In 2 patients, mast cell numbers were equal at contralateral sites and only in one, triamcinolone-treated skin had a reduction of mean counts to 39 cells/field, compared to 64 on the IFNa-treated side. 4. Discussion This study was aimed at exploring the possible efficacy of topically applied IFNa in a small group of patients, compared to triamcinolone, LCD, bland cremes and a gel. It demonstrates clearly that the IFNa-gel shows no superiority over the other agents with the methods employed. As would be expected, triamcinolone caused a more rapid clearing of the lesions, although it had no effect on the itch. This finding is surprising, may however relate to the fact that only a small part of the involved skin was treated and that discrimination from the general pruritus was difficult for the patient. A number of methodological problems might account for the lack of effects observed, such as differences in tolerance of the agents and their vehicles, lack of sufficient penetration of the
155
IFNa-gel and an insufficiently long duration of treatment. Since all formulations were generally well tolerated, the first factor can be excluded. Regarding penetration, no data are available for the IFN formulation used in human skin. Since barrier function is however known to be defective in eczematous skin, since gels penetrate generally better than cremes, and since part of the pathology in atopic eczema is found in the epidermis, one might expect that the lack of efficacy of IFNa is not due to this factor. It was hoped to gain further clues in this regard with the mast cell counts, since we have previously noted dramatic increases of mast cells after intralesional injections of IFNa in cutaneous leukemic and lymphomatous infiltrates [lo]. Although mast cell numbers were increased in all three patients, as described before [ll], this held for both biopsy sites, and the reduction in numbers in one patient at the triamcinolone-treated site would best be explained by the known effect of steroids on mast cell numbers [12]. The lack of tissue eosinophils in both steroid- and IFN-treated lesions might however indicate that both drugs induced this depletion [81 since the present patients had an eosinophilia at the start of therapy. Regarding duration of treatment, we cannot be absolutely sure whether a more extended treatment period might not have revealed benefits from IFNa over those of bland treatment, particularly as systemic treatment is generally done for a longer time period (L 2 months). Since steroids were however clearly superior to IFNa during the 10 days of therapy, one should have detected any striking benefit of IFN during this period. It appears therefore questionable whether more extensive and protracted treatment trials are warranted on the basis of the present disappointing results. References [ll Rajka G. Essential aspects of atopic dermatitis. Berlin, Springer, 1989. 121von Joost T, Stolz E, Henle F. Efficacy of low-dose cyclosporin in severe atopic disease. Arch Dermatol 1987;123:166-167.
156
B. Cremer et al. /J. Eur. Acad. Dermatol. Venereal. 5 (1995) 153-156
[3] Pent J, Rousset F, Briere F, et al. IgE production by normal lymphocytes is induced by II-4 and suppressed by interferons gamma and alpha and prostaglandin E,. Proc Nat1 Acad Sci USA 1988;85:6880-84. [4] Souillet G, Rousset F, de Vries JE. Alpha-interferon treatment of patient with hyper IgE syndrome. Lancet 1989;1:1384. [5] Reinhold U, Wehrmann W, Kukel S, Kreysel HW. Recombinant interferon-gamma in severe atopic dermatitis. Lancet 1990;1:1282. [6] Torrelo A, Harto A, Sendagorta E, et al. Interferon-alpha-therapy in atopic eczema. Acta Derm Venereol (Stockh) 1992;72:370-372. [7] Kropp J-D, AIgermissen B, Buck S, Czarnetzki BM. A pilot study on the effect of interferon alpha in atopic eczema. Hautarzt, in press.
[8] Paukkonen K, Fraki J, Horsmanheimo M. Interferon-alpha treatment decreases the number of blood eosinophils in patients with severe atopic eczema. Acta Derm Venereol (Stockh) 1993;73:141-142. [9] Jullien D, Nicolas JF, Frappaz A, Thivolet J. Alpha interferon treatment of atopic eczema. Acta Derm Venereal (Stockh) 1993;73:130-132. [lo] Nowak F, Haas N, Grabbe J, et al. Zunahme von Mastzellen nach intralasionalen Interferon+Injektionen bei cutanen Lymphomen. Zbl Hautkr 1993;162,150-151. [ll] Mihm MC, Soter JRA, Dvorak HG, Austen F. The structure of normal skin and the morphology of atopic eczema. J Invest Dermatol 1976;67:305-312. [12] Larker RM, Schechter NM. Cutaneous mast cell depletion results from topical corticoid usage. J Immunol 1985;121:1516-1523
Journal of the European Academy of Dermatology and Venereology 5 (1995) 153-156
JEADV
Topical interferon alpha in atopic eczema Brigitte Cremer * , Corinna Kohlmus, Beate M. Czarnetzki Department of Dermatology,
University Clinic Rudolf virchow, Freie Universitiit Berlin, Augustenburgerplatz D 13344 Berlin, Germany
1,
Abstract Background On the basis of experimental and clinical data, interferon (Y might improve pathological alterations in atopic eczema. Systemic treatment with this drug is however cumbersome and fraught with side effects. Objective Since most patients with atopic eczema have only localized disease, we have decided to study the effect of topically applied interferon (Y in this disease. Design A pilot study was performed on 10 patients, using a single-blind, within-patient comparison. An interferon-cw2a gel formulation (150000 IU/g) was studied against triamcinolone acetonide, liquor carbonis detergens and bland cremes or gels with a twice daily application to the anticubital fossae over 10 days. Biopsies were taken from 3 patients for evaluation of treatment-induced histopathological changes. Results Improvement of eczema occurred most rapidly with triamcinolone whereas interferon (Y was as effective as other treatments and vehicle alone. No effect on pruritus was noted with any patient, Only two patients considered interferon (Ybetter than liquor carbonis detergens or bland cremes respectively. Mast cell numbers were elevated in all patient biopsies and were lower on the triamcinolone-treated site in only one patient. Conclusion Short-term treatment with topically applied interferon (Y is thus ineffective in atopic eczema. Keywords: Atopic eczema; Interferon a; Mast cells; Corticosteroids; Liquor carbonis detergens
1. Introduction The treatment of atopic eczema presents a major therapeutic challenge since all currently available treatment modalities suppress symp* Corresponding author.
toms only transiently or side effects are unacceptable [l]. Avoidance of allergens is the best preventive measure but is mostly impracticable. Since the basic pathology of atopic eczema involves defects in the immune system, with overactivity of IgE-dependent processes, treatment with immunomodulating agents such as cortico-
0926-9959/95/$09.50 0 1995 Elsevier Science B.V. AU rights resewed SSDZ 0926-9959(95)00081-X
154
B. Cremer et al. /J. Eur. Acad. Dennatol.
steroids and cyclosporin A has been found to be highly effective, although side effects prohibit long-term use of these agents [1,21. Interferons (IFN) have recently been reported to suppress IgE synthesis in vitro [3] and to possibly affect IgE levels and eczema in vivo [4]. Several clinical studies have since yielded no or only minor clinical benefits, no decrease of IgE levels, and only few changes in other laboratory parameters like eosinophil numbers [5-91. Treatment is generally well tolerated despite the cumbersome injections, with mostly only transient flu-like symptoms. Explanations for the discrepancy between in vitro and in vivo observations might be insufficient concentrations of the drug at the tissue level. Since the majority of patients with atopic eczema suffer from limited involvement of their skin and in order to obtain a higher local drug concentration, we have decided to conduct a pilot study using a gel formulation of IFNa in comparison with established, locally effective treatment modalities and bland formulations. 2. Methods Ten hospitalized patients (5 males and 5 females; mean age 38.5 and 23.5 yrs respectively) with mild to moderately severe atopic eczema agreed to participate in the study. All patients had a personal and 9 of them also a family history of atopic diseases. Mean serum IgE levels were 10000 IU/ml (range 600-35000) and mean serum eosinophilia 20%. No other abnormal laboratory findings were noted. An IFNa gel formulation at 150000 IU/g was prepared by the hospital pharmacist, mixing: 1. five ampules containing 3 mil IU IFNa2a (RoferonR); 2. hydroxyethylcellulose 10000, 2.5 g; 3. glycerol 85%, 10 g; 4. distilled water ad 100 (formulation kindly provided by Prof. R. Stadler, Minden, Germany). This formulation is stable at 4°C for 4 weeks. The gel was applied twice daily over 10 days on skin of the anticubital fossa. On the contralatera1 side, patients received the following substances at the same frequency: the gel base of the
Venereal. 5 (1995) 153-156
IFN formulation (2 patients); triamcinolone acetonide in adeps lanae, 0.1% (3 patients); liquor carbonis detergens 10% (2 patients); a bland creme base (3 patients). Blinding was for patients only. They were asked daily regarding itching and tolerance of the medication at each treated site, and the physician evaluated changes in intensity of local inflammation and extent of the lesions. At the end of treatment, three patients (all tested against triamcinolone) agreed to have biopsies taken which were processed for routine histology and stained with H&E and with toluidine blue O.l%, pH 0.5, overnight for mast cell counts. Biopsies from the same sites were taken from 3 non-atopic normal controls. Sections were evaluated by 3 independent observers and cell counts performed at 400 x magnification in at least two microscopic fields directly underlying the epidermis. Data are expressed as means f 1 standard deviation (SD). 3. Results All lesions improved within 5-6 days, except for triamcinolone acetonide-treated sites where healing occurred already within 3-4 days. The within-patient comparison of the two treated sites showed no differences in intensity of itching, except for increased pruritus in one patient treated with IFNa (Table 1). Regarding subjective tolerance, two patients considered the IFNa-gel better compared to LCD and bland creme, respectively, and one patient found the IFNa-gel worse than triamcinolone. Table 1 Comparison of clinical effects of IFNa-containing gel in comparison to either of the various agents shown above, applied to the contralateral antecubital fossa of patients with atopic eczema. Numbers indicate patients where the compared substance was better or worse than IFNa. In the remaining cases, effects were the same on both arms Agents tested against IFNa (N)
Pruritus
Eczema
Tolerance
Better Worse Better Worse Better Worse
Triamcinolone (3) 0 LCD (2) 0 Bland ointment (3) 0 Gel base (2) 0
0 0 1 0
3 0 1 0
0 1 0 0
1 2 0 0
0 0 0 0
B. Cremer et al. /.I. Eur. Acad. Dermatol. Venereol.5 (1995) 153-156 Table 2 Mast cell counts/microscopic field (4OOXmagn.) from biopsies of the antecubital fossa in patients after the lo-day treatment and in normal controls Biopsies (N) from Patients, IFNa-treated side (3) Patients, steroid-treated side (3) Normal controls (3)
Mast cell numbers Means f SD
Range
47.3 + 16.4
(25-64)
40.0 + 13.5
(24-57)
22.7* 2.6
(17-25)
On histological evaluation, all patients exhibited typical features of atopic eczema on H&E, compared to normal skin, despite the preceding treatment, with acanthosis and a moderate perivascular inflammatory infiltrate consisting of lymphocytes and macrophages. Eosinophils were not seen. Mast cell numbers were elevated in patient compared to normal skin (Table 2). Numbers were only slightly higher at IFNa compared to triamcinolone-treated sites, without reaching statistical significance. In 2 patients, mast cell numbers were equal at contralateral sites and only in one, triamcinolone-treated skin had a reduction of mean counts to 39 cells/field, compared to 64 on the IFNa-treated side. 4. Discussion This study was aimed at exploring the possible efficacy of topically applied IFNa in a small group of patients, compared to triamcinolone, LCD, bland cremes and a gel. It demonstrates clearly that the IFNa-gel shows no superiority over the other agents with the methods employed. As would be expected, triamcinolone caused a more rapid clearing of the lesions, although it had no effect on the itch. This finding is surprising, may however relate to the fact that only a small part of the involved skin was treated and that discrimination from the general pruritus was difficult for the patient. A number of methodological problems might account for the lack of effects observed, such as differences in tolerance of the agents and their vehicles, lack of sufficient penetration of the
155
IFNa-gel and an insufficiently long duration of treatment. Since all formulations were generally well tolerated, the first factor can be excluded. Regarding penetration, no data are available for the IFN formulation used in human skin. Since barrier function is however known to be defective in eczematous skin, since gels penetrate generally better than cremes, and since part of the pathology in atopic eczema is found in the epidermis, one might expect that the lack of efficacy of IFNa is not due to this factor. It was hoped to gain further clues in this regard with the mast cell counts, since we have previously noted dramatic increases of mast cells after intralesional injections of IFNa in cutaneous leukemic and lymphomatous infiltrates [lo]. Although mast cell numbers were increased in all three patients, as described before [ll], this held for both biopsy sites, and the reduction in numbers in one patient at the triamcinolone-treated site would best be explained by the known effect of steroids on mast cell numbers [12]. The lack of tissue eosinophils in both steroid- and IFN-treated lesions might however indicate that both drugs induced this depletion [81 since the present patients had an eosinophilia at the start of therapy. Regarding duration of treatment, we cannot be absolutely sure whether a more extended treatment period might not have revealed benefits from IFNa over those of bland treatment, particularly as systemic treatment is generally done for a longer time period (L 2 months). Since steroids were however clearly superior to IFNa during the 10 days of therapy, one should have detected any striking benefit of IFN during this period. It appears therefore questionable whether more extensive and protracted treatment trials are warranted on the basis of the present disappointing results. References [ll Rajka G. Essential aspects of atopic dermatitis. Berlin, Springer, 1989. 121von Joost T, Stolz E, Henle F. Efficacy of low-dose cyclosporin in severe atopic disease. Arch Dermatol 1987;123:166-167.
156
B. Cremer et al. /J. Eur. Acad. Dermatol. Venereal. 5 (1995) 153-156
[3] Pent J, Rousset F, Briere F, et al. IgE production by normal lymphocytes is induced by II-4 and suppressed by interferons gamma and alpha and prostaglandin E,. Proc Nat1 Acad Sci USA 1988;85:6880-84. [4] Souillet G, Rousset F, de Vries JE. Alpha-interferon treatment of patient with hyper IgE syndrome. Lancet 1989;1:1384. [5] Reinhold U, Wehrmann W, Kukel S, Kreysel HW. Recombinant interferon-gamma in severe atopic dermatitis. Lancet 1990;1:1282. [6] Torrelo A, Harto A, Sendagorta E, et al. Interferon-alpha-therapy in atopic eczema. Acta Derm Venereol (Stockh) 1992;72:370-372. [7] Kropp J-D, AIgermissen B, Buck S, Czarnetzki BM. A pilot study on the effect of interferon alpha in atopic eczema. Hautarzt, in press.
[8] Paukkonen K, Fraki J, Horsmanheimo M. Interferon-alpha treatment decreases the number of blood eosinophils in patients with severe atopic eczema. Acta Derm Venereol (Stockh) 1993;73:141-142. [9] Jullien D, Nicolas JF, Frappaz A, Thivolet J. Alpha interferon treatment of atopic eczema. Acta Derm Venereal (Stockh) 1993;73:130-132. [lo] Nowak F, Haas N, Grabbe J, et al. Zunahme von Mastzellen nach intralasionalen Interferon+Injektionen bei cutanen Lymphomen. Zbl Hautkr 1993;162,150-151. [ll] Mihm MC, Soter JRA, Dvorak HG, Austen F. The structure of normal skin and the morphology of atopic eczema. J Invest Dermatol 1976;67:305-312. [12] Larker RM, Schechter NM. Cutaneous mast cell depletion results from topical corticoid usage. J Immunol 1985;121:1516-1523